Protein kinases represent a large family of proteins, which play a central role in the regulation of a wide variety of cellular processes, thus maintaining control over cellular function. A partial list of such kinases includes Akt, Axl, Aurora A, Aurora B, Lck, Fyn, Lyn, Yes, dyrk2, epha2, fgfr3, flt-3, vegfr3, igf1r, IKK2, JNK3, Vegfr2, MEK1, MET, P70s6K, Plk1, RSK1, Src, TrkA, Zap70, cKit, bRaf, EGFR, Jak2, PI3K, NPM-Alk, c-Abl, BTK, FAK, PDGFR, TAK1, LimK, Flt3, Flt1, PDK1 and Erk.
Abnormal cellular responses triggered by protein kinase-mediated events produce a variety of diseases. These include autoimmune diseases, inflammatory diseases, neurological and neurodegenerative diseases, cancer, cardiovascular diseases, allergies and asthma, Alzheimer's disease and hormone-related diseases. Accordingly, there has been a substantial effort in medicinal chemistry to find protein kinase inhibitors that are effective as therapeutic agents.
Small molecule inhibitors of protein kinases like the Src kinases have been reported recently, but their effect on cytokinesis has yet to be investigated in detail.
The role of Src tyrosine kinase and its inhibitors has been reported in the literature. For example, Garcia et al. described activation of the Stat3 kinase by Src and JAK kinases in promoting growth regulation of human breast carcinoma cells (Oncogene, (2001), 20:2499-2513. Mukhopadhyay et al. showed hypoxic induction of human vascular endothelial growth factor expression through activation of c-Src (Nature [London], (1995), 375:577-581).
Bristol Myers Squibb described their drug, dasatinib, as a tyrosine kinase inhibitor that suppresses invasion and induces cell cycle arrest and apoptosis in squamous cell carcinoma and non-small cell lung cancer cells (Clin. Cancer Res., (2005), 11(19):6924-6932).
Serrels et al. disclosed the identification of potential biomarkers for measuring inhibition of Src activity in colon cancer cells with dasatinib (Mol. Cancer. Ther., (2006), 5(12):3014-3022). PP Takeda Pharmaceuticals Co., Ltd., disclosed pyrido-indole derivatives that are inhibitors of tyrosine kinases and cyclin-dependent kinases, and so are useful as antitumor, antibacterial and anti-viral agents (WO 2008/016184).
However, the need exists for a protein kinase inhibitor that is capable of inhibiting, modulating and/or regulating signal transduction by aberrant protein kinases, thereby effectively treating proliferative diseases such as cancers and cardiovascular, neurodegenerative, inflammatory, and endocrine-related diseases. It is also desirable for this protein kinase inhibitor to be useful in combination therapies for disease treatment and as a diagnostic tool.
These compounds of the present invention and pharmaceutical compositions comprising them are presented either individually or in kit form. Included in this invention also are processes for preparing the compounds that actively modulate or inhibit unregulated protein kinase activity.
Additional objects, features and advantages of the present invention will become apparent to those skilled in the art from the following description and claims.